During hematopoiesis, hematopoietic stem cells (HSCs) in bone marrow differentiate into common lymphocyte precursors (CLPs) and common myeloid precursors (CMPs). CMPs differentiate into cells of myeloid lineage, such as erythrocytes, megakaryocytes/platelets, neutrophils, eosinophils, basophils, monocytes, macrophages and dendritic cells. CLPs give rise to cells of lymphocyte lineage such as T cells, B cells and NK cells.
Functionally, blood cells comprise red blood cells, which supply oxygen to tissues, platelets, which control clotting, and leukocytes, which protect against infectious diseases and foreign substances. Leukocytes (white blood cells) include the white cells of the myeloid lineage such as neutrophils, eosinophils, basophils, and monocytes, as well as lymphocytes such as T-cells and B-cells. There are about 4,000-10,000 leukocytes per 1 μl of blood. The leukocyte population is generally made up of 50-60% neutrophils, 1-6% eosinophils, less than 1% basophils, 2-10% monocytes, and 20-30% lymphocytes. However, the level and composition of leukocytes can vary widely among individuals or in the same individual over time, depending on factors such as physical condition and inflammation status.
If the differentiation of HSCs into CMP cells is suppressed, the concentration of leukocytes in the blood will decrease below normal range, causing leukopenia. Leukopenia can be caused by bacterial or viral infection often. However, leukopenia can be also caused by aplastic anemia, leukemia, myelodysplastic syndrome (MDS) or other bone marrow disorders. While mild leukopenia will result in only minor deficiency in immune response, severe leukopenia can even cause sepsis.
As neutrophils are the most abundant leukocyte, leukopenia generally entails neutropenia. Neutrophils serve as the primary defense against infections by destroying bacteria in the blood. Patients with neutropenia are more susceptible to bacterial infections and are vulnerable to potentially lethal sepsis if the condition is not controlled. Absolute neutrophil count (ANC) varies by age and sex, with a normal range in adults of 1500 to 8000 cells per microliter (μl) of blood, although ANC in healthy adults is typically >2500 cells/μl. ANC <500 cells/μl is considered severe and is a very dangerous condition, correlating with a high risk of serious infection. Neutropenia may be caused by many things, e.g., cancer or other diseases that damage bone marrow, congenital disorders characterized by poor bone marrow function, viral infections that disrupt bone marrow function, autoimmune disorders that destroy neutrophils or bone marrow cells, overwhelming infections that use up neutrophils faster than they can be produced, or drugs that destroy neutrophils or damage bone marrow. Many anti-cancer drugs as well as radiation therapy for cancer may cause direct dose-dependent bone marrow suppression. Other anticancer drugs incite immune-mediated destruction of progenitor cells within the bone marrow compartment and in some cases increased destruction or clearance of peripheral neutrophils.
Various cytokines are involved in hematopoiesis. Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the hematopoietic precursor cells in the bone marrow to proliferate and differentiate into mature granulocytes and stem cells and release them into the bloodstream. It also induces release of hematapoietic stem cells (HSCs) from the bone marrow into the blood stream, although it does not specifically stimulate these cells. In humans, it exists in two active forms, the more abundant of which is 174 amino acids long; the other is 177 amino acids long. The pharmaceutical analogs of naturally occurring G-CSF are recombinant forms of the human 174-amino acid peptide (rhG-CSF), and include:                filgrastim (e.g. Neupogen® from Amgen), which made in E. coli, having the same activity, but differing from the natural glycoprotein in having an N-terminal methionine residue and lacking glycosylation;        lenograstim (e.g., Granocyte® from Chugai), which is made in mammalian cells (Chinese Hamster Ovary (CHO) cells), and so is essentially indistinguishable from human G-CSF;        pegfilgrastim, a PEGylated form of filgrastim, (e.g., Neulasta® from Amgen and Neulastim® from Roche), having a 20 kD monomethoxypolyethylene glycol moiety covalently bound to the N-terminal methionyl residue of filgrastim, which increases solubility and duration of action compared to filgrastim.        
These drugs are approved in the US and many other countries to treat and mitigate neutropenia, primarily in cancer patients receiving chemotherapy, e.g., for one or more of the following indications                to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia;        to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid lymphoma;        to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation;        to mobilize hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis, which can then be transplanted into the patient following myeloablative chemotherapy, which may result in a decreased need for supportive care;        to reduce the incidence and duration of sequelae of neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia        
Neupogen® is generally given at doses of 4 to 8 mcg/kg/day, up to 10 mcg/kg/day. Higher doses, up to 138 mcg/kg/day have been administered without toxic effects, but there is a flattening of the dose response curve above daily doses of greater than 10 mcg/kg/day. Side effects of Neupogen® and other forms of G-CSF may include mild-to-moderate bone pain after repeated administration, local skin reactions at the site of injection, allergic reactions, enlarged or ruptured spleen, alveolar hemorrhage, acute respiratory distress syndrome (ARDS), hemoptysis, and (in patients with pre-existing sickle cell disorders) sickle cell crises. G-CSF drugs are generally not given in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome, as they could potentially spur the growth of cancer cells.
Platelets, also called thrombocytes, are colorless blood cells that help the blood to clot. Normal human platelet counts range from 130,000-400,000 platelets per microliter (μl) of blood. As in the case of neutropenia, if the differentiation of HSCs into CMPs is suppressed, or if platelets are destroyed, for example as a result of an autoimmune condition, the concentration of platelets in the blood may drop below normal ranges (thrombocytopenia). A platelet count of <50,000 platelets/μl of blood is considered a serious condition, and with a count of <20,000 platelets/μl of blood, life-threatening internal bleeding can occur spontaneously. Thrombocytopenia has few symptoms until the platelet count is extremely low, when impairment to clotting is evidenced by spontaneous bruising, bruising after very mild trauma, petechia (red or purple spots on the skin caused by tiny hemorrhages in the skin and mucous membranes), and excessive bleeding from minor cuts, nosebleeds or brushing the teeth. Other symptoms may include malaise, fatigue and general weakness (with or without accompanying blood loss). Thrombocytopenia may be caused by, e.g., bacterial or viral infection, cirrhosis, chemotherapy or radiation therapy, acute leukemia, aplastic anemia, or autoimmune conditions, or may be a side effect of various medications. Like neutropenia, thrombocytopenia is a frequent side effect of chemotherapy or radiation therapy for cancer.
Thrombocytopenia may cause, exacerbate or be co-morbid with anemia. Anemia may be caused by active bleeding, for example from heavy menstrual bleeding, wounds, gastrointestinal ulcers, or cancers such as cancer of the colon which may slowly ooze blood, and such bleeding may be caused or exacerbated by thrombocytopenia. Anemia is also common in patients suffering from chronic disease, poor nutrition, and kidney failure, all of which may occur in cancer patients receiving chemotherapy or radiation therapy.
Multiple myeloma (MM) is a cancer of the plasma cells, which produce antibodies. Myeloma prevents the normal production of antibodies, leaving the immune system weakened and the patient susceptible to infection, while producing defective antibodies that may cause kidney damage. The multiplication of myeloma cells also interferes with the normal production and function of red and white blood cells, and the myeloma cells commonly produce substances that cause bone destruction, leading to bone pain and/or fractures. Multiple myeloma is specifically stimulated by G-CSF. Acute myeloid leukemia (AML), also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL), is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults. The myelodysplastic syndromes (also known as MDS or myelodysplasia) are characterized by ineffective production (or dysplasia) of the myeloid class of blood cells. Patients with MDS can develop severe anemia and require blood transfusions. In some cases, the disease worsens and the patient develops cytopenias caused by progressive bone marrow failure. Chronic myelogenous leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found.
Bone marrow malignancies, such as MM, AML, MDS and CML, may be induced or stimulated by granulocyte-colony stimulating factor (G-CSF). While in a few cases, G-CSF has been deliberately used to stimulate cancer cell proliferation in these types of cancers, in order to enhance their susceptibility to chemotherapeutic agents (which generally target proliferating cells), recombinant G-CSF drugs (e.g., filgrastim, lenograstim, or pegfilgrastim) are not generally a good option to treat chemotherapy-induced neutropenia in patients recovering from these types of cancers.
For example, lenalidomide (Revlimid®) is a derivative of thalidomide, used to treat multiple myeloma, myelodysplastic syndromes and other cancers. Lenalidomide has significantly improved overall survival in myeloma (which generally has a poor prognosis), but the drug is quite toxic. Myelosuppression leading to severe neutropenia and thrombocytopenia, is the major dose limiting toxicity.
New approaches to treatment and management of neutropenia and thrombocytopenia are needed, for example to permit more aggressive chemotherapy at higher doses and/or for longer duration than is currently safe, and particularly in patients having G-CSF-inducible cancers, whose neutropenia cannot be managed with G-CSF.
Deer antler is a traditional Asian medicine, prepared by drying uncornified antler of a deer. Deer antler has been acclaimed to have various medical effects, such as growth- and development-promoting effects, promoting hematopoietic function, treating nervous breakdown, beneficial to cardiac insufficiency, improving the function of five viscera and six entrails, as described in the Dong-eui Bogam, a Korean medical book first published in 1613. It has been reported that certain components of deer antler, including rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol (PLAG) obtained from chloroform extracts of the deer antler, have growth-stimulating activities of hematopoietic stem cells and megakaryocytes (WO 99/26640). It is also reported that monoacetyldiacylglycerol derivatives which are active components of the deer antlers are effective in treating autoimmune diseases, sepsis, cancers such as bile duct cancer, kidney cancer or malignant melanoma, and so on (WO 2005/112912).